The enzyme, dipeptidyl peptidase IV (DPP-IV), which is identical with the lymphocyte surface glycoprotein CD26, a polypeptide with the molecular mass of 110 k Dalton, is formed in the tissues and organs of mammals. This enzyme can be found, among others, in the liver, in the Langerhans islands, in the renal cortex, in the lungs, and in certain tissues of the prostate and small intestine. Significant DPP-IV activity can be observed furthermore in the body liquors (as for instance in the plasma, serum and urine). DPP-IV is a serine protease type enzyme, which has the unique specificity to cleave dipeptides from the N-terminals of the peptides, where the pre-terminal dipeptide is prolyl-alanine, or hydroxy-proline.
DPP-IV enzyme is responsible for the decomposition of the glucagon-like peptides, peptide-1 (GLP-1) and peptide-2 (GLP-2) in the body. The enzyme GLP-1 strongly stimulates the insuline production of the pancrease, thus it has a direct, favourable effect on the glucose homeostasis, therefore DPP-IV inhibitors are suitable for the treatment of non-insuline dependent diabetes mellitus (NIDDM) and for the treatment or prophylaxis of other diseases connected to the DPP-IV enzyme activity, including but not limited to diabetes, obesity, hyperlipidemia, dermatological or mucous membrane disorders, psoriasis, intestinal distress, constipation, autoimmune disorders such as encephalomyelitis, complement metiated disorders such as glomerulonephritis, lipodystrohy and tissue damage, psychosomatic, depressive and neuropsychiatric disease such as anxiety, depression, insomnia, schizophrenia, epilepsy, spasm and chronic pain, HIV infection, allergies, inflammation, arthritis, transplant rejection, high blood pressure, congestive heart failure, tumors and stress-induced abortions. There are a number of DPP-IV inhibitors known in the literature, but they have disadvantages as regards their activity, toxicity, physico-chemical properties, stability and duration of action.
Our aim was to prepare new, effective and safe DPP-IV inhibitors having advantageous physico-chemical and biological properties.